Since the 1970s, biodegradable polymeric materials have been extensively used in medical applications, particularly in biodegradable surgical sutures, medical adhesives, biodegradable bone fixation devices, sustained drug release, recent research in biodegradable stents, etc.
Biodegradable polymeric materials are thermoplastic or cross-linked materials. Thermoplastic biodegradable polymeric materials feature long-chain linear molecules. While such materials are soluble in compatible solvents and can be easily molded and processed using injection, extrusion and other common forming technologies, they suffer from an obvious disadvantage of exhibiting stress relaxation behavior.
Cross-linked polymers are three-dimensional networks formed by adding crosslinking agents during the polymerization of monomer or by introducing crosslinkable reactive groups in molecular chains of a linear polymer and then inducing the reaction of the reactive groups on different chains of the polymer by means of radiations, ultraviolet (UV) light, heat or the like. Cross-linked polymers swell rather than dissolving in compatible solvents. Their molding can be performed either before or after the crosslink reaction and the latter case requires the use of special equipment. Although cross-linked polymers exhibit higher structural and dimensional stability and reduced stress relaxation behavior compared to linear polymers, they are disadvantageous in requiring special equipment and technologies for their molding.
In previous research, synthesis of cross-linked polymers was mostly for producing hydrogels and investigating shape memory behavior of the materials. Because such synthesis usually involved complicated multi-step synthesis of pre-polymers, its control was difficult, making it only suitable to be carried out in laboratories for research purposes. Additionally, since materials used in, and by-products produced from, such synthesis were toxic and difficult to be completely removed, use of them in the medical field has not been considered.
In References (1) and (2), the authors introduce their synthesis of cross-linked poly(butyl acrylate) networks and investigations of shape memory behavior of the materials. These cross-linked polymers are both prepared by crosslinking an optically or thermally crosslinkable polycaprolactone macromonomers obtained from methacryloyl chloride in the presence of tetrahydrofuran (or 2-dichloroethane) and an excess of triethylamine as a catalyst. During the reaction, a side reaction will occur between methacryloyl chloride and excessive triethylamine, and triethylamine hydrochlorides remaining in the product are difficult to be completely removed. The authors also propose a cross-linked shape memory polymer defined in claims 1 and 17 of patent Reference (3). The major purpose of this application is for claiming the protection of the cross-linked shape memory polymer which has at least two soft polymeric segments. In addition, exemplary cross-linked shape memory polymers presented in the application exhibit an elastic modulus of only about 71 MPa. With similarity to those of References (1) and (2), in this polymer material, only the cross-linked segments are biodegradable, while the butyl acrylate content that makes a predominant part is non-biodegradable. Further, the preparation of this cross-linked polymer is also associated with the issues of involving multiple synthesis steps, causing remains of by-products and using excessive solvents, arising from the use of the same prepolymer synthesis process as those of References (1) and (2).
Claims 1 and 12 of patent Reference (4) describe a cross-linked biodegradable polymer prepared based on a polymer made from the polycondensation of glycerol and a bifunctional diacid as monomers. This biodegradable polymer has a very low elastic modulus that is ≤5 MPa.
Patent Reference (5) discloses a cross-linked polyester elastomer. However, this polymer also has a very low elastic modulus of <1.5 MPa.
Existing stents used in the treatment of postoperative vascular restenosis and other conditions typically include metal stents, drug-eluting metal stents and biodegradable metal stents. Although the continuously progressing technology in the field of metal stents has addressed the issue of post-PTCA elastic recoil, intimal hyperplasia and other complications caused by intimal injury and the presence of metallic foreign bodies still remain unsolved. Drug-eluting metal stents can achieve an extent of intimal hyperplasia inhibition and a reduced incidence of restenosis, but due to the inevitable stimulating effect as metallic foreign bodies, their use is associated with prolonged administration of antiplatelet drugs. Further, metal stents may impede beneficial vascular remodeling after implantation.
The occurrence of restenosis is strongly time-dependent. Biodegradable stents are temporary stents which stay in vivo across specific pathological processes and disappear after fulfilling their therapeutic functions, thus avoiding exerting a long-term foreign body effect on the human body. In addition, biodegradable stents can be further used as carriers for sustained drug release and ultimately achieve intimal hyperplasia inhibition through the drug release.
For these reasons, biodegradable stents have received considerable attention. In the recent twenty years, many biodegradable stents have been made from various polymeric materials, such as L-polylactic acids (i.e., poly(L-lactide)), DL-polylactic acids (i.e., poly(L-lactide-co-D-lactide)), copolymers of L-lactide and other monomers, polycaprolactones and other thermoplastic polymeric materials, as well as their blends, or braided from fibers of these materials. In these materials, poly(L-lactide) are most studied. During the period from 1998 to 2000, human experiments related to poly(L-lactide)-based coronary stents were conducted in Japan. In 2006, Abbott commenced human experiments in Europe about a poly(L-lactide)-based drug-eluting coronary stent and acquired the CE Mark in 2011, leading to the debut of the first biodegradable cardiovascular stent product allowed to enter the market. For more information in this regard, reference can be made to non-patent References 1-14 and patent references such as, for example, U.S. Pat. Nos. 5,059,211A and 5,306,286A describing a biodegradable stent formed from a roll-up polymeric sheet, US20020143388A1, US20020019661A1, U.S. Pat. No. 6,338,739B1 and US20010029398A1 describing biodegradable stents formed from a blend of two biodegradable thermoplastic polymers, US20030144730A1 and US20050177246A1 describing a helical or tubular stent formed from absorbable fibers each having an inner core and an outer layer, and US20020188342A1 describing a braided stent formed from resorbable fibers.
However, most of commonly used polymeric materials have drawbacks as follows: insufficient mechanical strength, which makes stents made of such materials less resistant to radial compressing forces and easily to be broken by gripping pressure; stress relaxation behavior, which results in unstable performance of the stents and radial strength decreasing with time; and short shelf-lives. Compared to metallic materials, polymeric materials have much weaker mechanical properties. In contrast to elastic moduli of most metallic materials that are higher than 100 GPa, those of strongest polymeric materials are on the order of several GPa and those of aforementioned polylactic acid polymers for making biodegradable vascular stents are about 2.7 GPa. For example, US20070129784A1 describes a stent made from a shape memory polymer having cross-linked polymer. The polymer can be either a thermoplastic polymer network or a polymer blend exhibiting shape memory characteristics. However, polymer networks have very undesirable mechanical properties, for example, low elastic moduli in the range of 0.5-50 MPa, and show stress relaxation behavior, i.e., gradually decreasing stress with time at a given temperature and strain rate. In order to reduce the effect of such shortcomings, polymeric stents are typically made to have walls that are much thicker than those of metallic ones. This not only leads to non-compact dimensions of the stents but also renders them unable to provide a biodegradation rate compatible with the duration of healing of a vascular lesion where the stent is deployed.
Therefore, the conventional cross-linked polymers cannot meet the requirements for use as materials for developing medical devices in terms of mechanical properties, biocompatibility and controlled biodegradation. In addition, the complexity and excessive use of solvents in their synthesis have imposed a great challenge for controlled mass production. There is thus a need for novel cross-linked biodegradable polymers and methods of manufacturing them. Further, there is also a need for biodegradable vascular stents having sufficient mechanical strength, high elastic moduli at body temperature, compact sizes, sufficient radial strength for supporting blood vessels, minimal compression in blood vessels, stable performance, high resistance to gripping pressure, adequate shelf-lives and capability of providing a biodegradation rate compatible with the duration of healing of the vascular lesion.